Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of 13%. Over 80% of PDAC patients are solely offered systemic chemotherapy due to late-stage disease, and resistance is rapidly acquired. FOLFIRINOX chemotherapy offers an 11.1-month median survival compared to 6.8 months with Gemcitabine. Rapid resistance to FOLFIRINOX, with the lack of alternative targeted therapies, ultimately results in patients succumbing to the disease. My project aims to identify mechanisms by which PDAC cells acquire resistance to FOLFIRINOX and investigate interventions to enhance and/or reinstate FOLFIRINOX sensitivity.
Multiple patient derived xenografts (PDXs) from the Avner Australian Pancreatic Cancer Matrix Atlas (APMA) have been exposed to 11 - 15 rounds of FOLFIRINOX (or vehicle) in vivo. Quantitative mass spectrometry proteomic and RNA sequencing of treated tumours has revealed pathways and proteins operating in the chronically treated tumours and the surrounding pancreatic tumour microenvironment.
Matched treatment naïve and FOLFIRINOX-treated cell lines derived from the PDXs are invaluable tools to validate identified targets via gene knockdown and pharmacological intervention. The labs proven in vitro 3D models allow us to assess the sensitivity of cancer cells to FOLFIRINOX during primary tumour growth and invasion. Furthermore, orthotopic (intrapancreatic) models and intravital imaging and biosensor technology will allow us to assess targeting in live tumours and metastatic sites in real time.
It is hoped that targeting identified proteins will re-sensitize tumours to FOLFIRINOX chemotherapy.